Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD
Yewei Wang, … , Ping Zhang, Geoffrey R. Hill
Yewei Wang, … , Ping Zhang, Geoffrey R. Hill
Published June 3, 2024
Citation Information: J Clin Invest. 2024;134(11):e170125. https://doi.org/10.1172/JCI170125.
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Research Article Immunology

Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD

Abstract

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A–secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.

Authors

Yewei Wang, Md Ashik Ullah, Olivia G. Waltner, Shruti S. Bhise, Kathleen S. Ensbey, Christine R. Schmidt, Samuel R.W. Legg, Tomoko Sekiguchi, Ethan L. Nelson, Rachel D. Kuns, Nicole S. Nemychenkov, Erden Atilla, Albert C. Yeh, Shuichiro Takahashi, Julie R. Boiko, Antiopi Varelias, Bruce R. Blazar, Motoko Koyama, Simone A. Minnie, Andrew D. Clouston, Scott N. Furlan, Ping Zhang, Geoffrey R. Hill

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Figure 9

CSA-expanded TCM preferentially mediate late GVHD.

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CSA-expanded TCM preferentially mediate late GVHD. Male B6D2F1 recipient...
Male B6D2F1 recipients were transplanted with 5 × 106 B6 TCD BM (CD45.2 or CD45.1), 1 × 106 B6 CD4+ T cells (WT or Il17aeYFP, CD45.2, CD90.2), and 0.15 × 106 Marilyn CD4+ TCR Tg T cells (CD45.2, CD90.1) followed by CSA (50 mg/kg) from day 0. Spleen and mesenteric lymph nodes were isolated on day +7 and sorted as CD4+ TEM and TCM. Equal numbers of sort-purified CD4+ TEM and TCM (5 × 105 per mouse) were adoptively transferred into secondary BMT recipients (male B6D2F1) of a parallel experiment which had been transplanted with TCD BM. Clinical scores were undertaken weekly and analysis was conducted at 28 days after T cell transfer. (A) Experimental schema (created with BioRender; biorender.com). (B) Clinical scores. (C) Pathology scores in the skin and representative images. (D and E) Adoptively transferred T cells were identified by congenic markers following enzymatic digestion of the skin tissue. (D) Numbers of transferred Marilyn Tg and polyclonal CD4+ T cells (relative to the TEM group). (E) Numbers of Il17aeYFP+ polyclonal CD4+ T cells in the skin with concatenated flow cytometric plots in the skin and the graft. (B–D) n = 10, 8, and 6 per group from 2 experiments; (E) n = 5, 5, and 2 per group from 1 experiment. Data are presented as mean ± SEM and analyzed with 2-way ANOVA (B) or 2-tailed t test (C–E). *P < 0.05; **P < 0.01; ***P < 0.001.